Prenatal screening and diagnosis are a routine part of antenatal care. Currently, prenatal diagnosis of genetic and chromosomal conditions involves invasive testing, such as amniocentesis or chorionic villus sampling (CVS), performed from 11 weeks gestation and carrying a ˜1% risk of miscarriage. The existence of circulating cell-free DNA in maternal blood (Lo et al., Lancet 350:485-487 [1997]) is being exploited for developing noninvasive processes that use fetal nucleic acids from a maternal peripheral blood sample to determine fetal chromosomal aneuploidies e.g. trisomy 21 (Fan H C and Quake S R Anal Chem 79:7576-7579 [2007]: Fan et al., Proc Natl Acad Sci 105:16266-16271 [2008]). These methods offer an alternative and safer source of fetal genetic material for prenatal diagnosis, and could effectively pronounce the end of invasive procedures.
Next Generation Sequencing (NGS) technologies have been used to determine entire human genome sequences (Levy et al. PLoS Biol 55, e254 [2007]; Wheeler et al. Nature 452:872-876 [2008]; Bentley et al., Nature 456:53-59 [2008]), and a broad interest exists in using NGS technologies for whole genome sequencing (WGS) to better understand human genetic variation and genome-related diseases, and ultimately to guide discoveries and decisions about the health of individuals. The extensive public genome-wide database of patterns of common human sequence variation provided by the International HapMap Project, and the increasing accessibility to whole genome sequencing technologies, will lead to the identification of new therapeutic targets and the development of targeted interventions for an individuals' medical care.
An additional need that remains is for identifying the disorder-associated genetic variations when two or more individual genomes are intermixed in a clinical sample e.g. mixtures of fetal and maternal genomes in biological fluid samples obtained from the mother, and mixtures of euploid and aneuploid genomes derived from cells of cancer patients.
The present invention addresses the need by providing a method for identifying polymorphisms in mixtures of genomes present in samples that can be obtained by noninvasive means. The method can be used for the non-invasive identification of multiple disease-associated polymorphisms in a variety of fields including but not limited to prenatal diagnostics, and oncology.